Calcium-dependent antigen binding as a novel modality for antibody recycling by endosomal antigen dissociation

Monoclonal antibodies have become a general modality in therapeutic development, and a variety of monoclonal antibodies targeting soluble antigens have been developed. However, even with infinite binding affinity to an antigen, a conventional antibody can bind to the antigen only once and results in an increase in total plasma antigen concentration in vivo. This antibody-mediated antigen accumulation generally occurs because the clearance from circulation of an antibody-antigen complex is much slower than that of a free antigen. This limitation has recently been overcome by sweeping antibodies, which are capable of actively eliminating soluble antigens from circulation. A sweeping antibody incorporates two antibody engineering technologies: one is variable region engineering to enable the antibody to bind to an antigen in plasma and dissociate from the antigen in endosome (after which the antigen undergoes lysosomal degradation), and the other is constant region engineering to increase the cellular uptake of the antibody-antigen complex into endosome. By enhancing the elimination of soluble antigens from circulation, sweeping antibodies can therapeutically target soluble antigens that conventional antibodies cannot. This review discusses the features, engineering technologies, advantages, and applications of sweeping antibodies that target soluble antigens.

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“…3B). These data confirmed that both pH and calcium-dependent antigen-binding antibody can dissociate an antigen within the endosome (53).…”

Section: Sweeping Antibody With Fc Engineering To Increase Fccr Bindingsupporting

confidence: 72%

Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation

Igawa¹,

Haraya

Hattori³

2016

Immunological Reviews

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“…Up-front screening of antibodies with different binding affinities for target at neutral and acidic pH is another effective strategy for isolating antibodies with improved PK/PD properties. This method, in combination with subsequent engineering of variable domain to optimize affinity to C5, pH dependent binding, stability and solubility as well as the introduction of M428L/N434A mutations to enhance FcRn binding, was used to produce the anti-C5 antibody, SKY59, which has a prolonged half-life in cynomolgus monkeys [20].…”

Section: Plos Onementioning

confidence: 99%

Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5

et al. 2020

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Complement is a key component of the innate immune system. Inappropriate complement activation underlies the pathophysiology of a variety of diseases. Complement component 5 (C5) is a validated therapeutic target for complement-mediated diseases, but the development of new therapeutics has been limited by a paucity of preclinical models to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of candidate therapies. The present report describes a novel humanized C5 mouse and its utility in evaluating a panel of fully human anti-C5 antibodies. Surprisingly, humanized C5 mice revealed marked differences in clearance rates amongst a panel of anti-C5 antibodies. One antibody, pozelimab (REGN3918), bound C5 and C5 variants with high affinity and potently blocked complement-mediated hemolysis in vitro. In studies conducted in both humanized C5 mice and cynomolgus monkeys, pozelimab demonstrated prolonged PK and durable suppression of hemolytic activity ex vivo. In humanized C5 mice, a switch in dosing from in-house eculizumab to pozelimab was associated with normalization of serum C5 concentrations, sustained suppression of hemolytic activity ex vivo, and no overt toxicity. Our findings demonstrate the value of humanized C5 mice in identifying new therapeutic candidates and treatment options for complement-mediated diseases. OPEN ACCESS Citation: Latuszek A, Liu Y, Olsen O, Foster R, Cao M, Lovric I, et al. (2020) Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5. PLoS ONE 15(5): e0231892. https://doi.org/10.

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“…Recent advances in antibody-engineering technology make it possible to develop not only target-specific therapeutics but also antibodies with various functions, such as bispecific target-binding, agonistic activity, conditional target-binding properties, and effector cell redirection826272829. Of these antibody-based therapeutics, TRABs are attracting attention in the field of cancer immunotherapy8.…”

Section: Discussionmentioning

confidence: 99%

Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics

Ueda¹,

Wada²,

Kinoshita³

et al. 2017

Sci Rep

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T cell–mediated immunotherapy is an attractive strategy for treatment in various disease areas. In this therapeutic approach, the CD3 complex is one of the key molecules to modulate T cell functions; however, in many cases, we cannot evaluate the drug candidates in animal experiments because the therapeutics, usually monoclonal antibodies specific to human CD3, cannot react to mouse endogenous Cd3. Although immunodeficient mice transfused with human hematopoietic stem or precursor cells, known as humanized mice, are available for these studies, mice humanized in this manner are not completely immune competent. In this study we have succeeded in establishing a novel mouse strain in which all the three components of the Cd3 complex — Cd3ε, Cd3δ, and Cd3γ — are replaced by their human counterparts, CD3E, CD3D, and CD3G. Basic immunological assessments have confirmed that this strain of human CD3 EDG–replaced mice are entirely immune competent, and we have also demonstrated that a bispecific antibody that simultaneously binds to human CD3 and a tumor-associated antigen (e.g. ERBB2 or GPC3) can be evaluated in human CD3 EDG–replaced mice engrafted with tumors. Our mouse model provides a novel means to evaluate the in vivo efficacy of human CD3–mediated therapy.

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Calcium-dependent antigen binding as a novel modality for antibody recycling by endosomal antigen dissociation

Cited by 25 publications

References 27 publications

Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation

Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation

Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5

Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics

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